1. Field of the Invention
This invention relates to a method of restoring ideal population-based body composition in obese mammals or preventing obesity especially in humans.
2. Description of Background and Related Art
Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease. Rissanen et al., British Medical Journal, 301: 835-837 (1990).
Obese subjects tend to have low basal levels of growth hormone (GH) and fail to secrete significant amounts of GH in response to a variety of stimuli, including growth hormone releasing hormone (GHRH). Williams, New Engl. J. Med., 311: 1403 (1984) Kopelman, Clin. Endocrinol., 23: 87 (1985); Kopelman, Clin. Endocrinol., 24: 157 (1986) Loche, Clin. Endocrinol., 27: 145 (19871) Ghigo et al., Metabolism, 41: 560-563 (1992). The GH responsiveness to GHRH in obese rats shows sexual dimorphism. Cocchi et al., Pharmacol. Res., 25: Suppl. 2, 336-337 (1992). This failure to secrete GH has been postulated to be the result of a hypothalamic disorder (Kopelman, 1986, supra), leading to a chronic state of somatostatin hypersecretion. Cordido, J. Clin. Endocrinol. Metab., 68: 290 (1989). This defect in GH secretion appears to be a result rather than a cause of obesity, since it is, at least in part, reversible with weight reduction.
While it has been suggested that the refractoriness of obese subjects to release GH is due to the feedback inhibition operated by the elevated plasma levels of insulin-like growth factor (IGF-I) (Loche et al., Clin. Endocrinol., 27: 145-153 [1987]), in fact, no correlation was found between IGF-I and indices of overweight. Cordido et al., Horm. Res., 36: 187-191 (1991). Thus, adiposity is not associated with a decline in IGF-I levels. Hochberg et al., Metabolism, 41: 106-112 (1992); Gama et al., Clin. Chim. Acta, 188: 31-38 (1990); Rosskamp et al., Eur. J. Pediatr., 146: 48-50 (1987). Further, impaired hGH stimulation in obese human subjects is not explained by an altered relationship between hGH and IGF-I levels. Jungmann et al., Med. Klin., 86: 237-240 (1991). Nor does reduction in circulating insulin levels lead to a higher ability to secrete GH. Chalew et al., Inter. J. Obesity, 16:459-463 (1992).
Certain diseases such as diabetes mellitus, especially adult onset or Type II diabetes, show a much higher prevalence of obesity. It has been found that low IGFBP-1 levels in obesity are related to elevated insulin levels, which are, in turn, related to body fat distribution and insulin resistance. The chronically depressed levels of IGFBP-1 may promote IGF bioactivity as well as its feedback regulation of GH secretion, thus contributing to the metabolic and mitogenic consequences of obesity. Conover et al., J. Clin. Endocrinol. Metab., 74: 1355-1360 (1992).
Existing therapies for obesity include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and surgery. Jung and Chong, Clinical Endocrinology, 35: 11-20 (1991); Bray, Am. J. Clin. Nutr., 55: 538S-544S (1992). Protein-sparing modified fasting has been reported to be effective in weight reduction in adolescents. Lee et al., Clin. Pediatr., 31: 234-236 (April 1992). Caloric restriction as a treatment for obesity causes catabolism of body protein stores and produces negative nitrogen balance. Protein-supplemented diets, therefore, have gained popularity as a means of lessening nitrogen loss during caloric restriction. Because such diets produce only modest nitrogen sparing, a more effective way to preserve lean body mass and protein stores is needed. In addition, treatment of obesity would be improved if such a regimen also resulted in accelerated loss of body fat. Various approaches to such treatment include those discussed by Weintraub and Bray, Med. Clinics N. Amer., 73: 237 (1989); Bray, Nutrition Reviews, 49: 33 (1991).
GH plays an important role in the regulation of somatic growth and metabolism. The metabolic effects of GH have been divided into early insulin-like effects, associated with enhanced glucose utilization and increased amino acid transport, and into anti-insulin-like effects, associated with the stimulation of lipolysis and depression of glucose utilization. GH promotes nitrogen conservation. Bray et al., J. Clin. Endocrinol. Metab., 33: 293 (1971).
IGF-I production is under the dominant stimulatory influence of GH, and some of the IGF-I binding proteins are also influenced by GH. See Tanner et al., Acta Endocrinol., 84: 681-696 (1977); Uthne et al., J. Clin. Endocrinol. Metab., 39: 548-554 (1974). For general reviews of IGF-I, see Baxter, Advances in Clinical Chemistry, 25: 49 (1986); Clemmons and Underwood, Clinics in Endocrin. and Metab., 15: 629 (1986). The use of IGF-I and GH by injection to produce weight gain and to have anabolic and growth-promoting effects in mammals, including diabetic patients, is disclosed by U.S. Pat. No. 5,126,324 issued Jun. 30, 1992.
GH is known to accelerate lipolysis in animals as well as in normal and obese humans. Raben and Hollenberg, J. Clin. Invest., 38: 484 (1959); Mautalen and Smith, J. Clin. Endocrinol. Metab., 25: 495 (1965); Felig et al., J. Clin. Invest., 50: 411 (1971); Jorgenson, Endocr. Reviews, 12, (1991); Martin et al., Inter, J. Obesity, 13: 327-335 (1989); Pfadt and Angulo, Arch. Dis. Child., 66: 1261 (1991); Jeevanandam et al., Surgery, 111: 495-502 (1992). GH was administered with a phenylethane derivative to increase weight gains and anti-lipogenic activity in animals. U.S. Pat. No. 4,792,546 issued Dec. 20, 1988. A lipolytic composition utilizing a growth factor such as nerve growth factor, epidermal growth factor, and fibroblast growth factor is described in WO 92/11838 published 23 Jul. 1992. The possibility of using GH to treat obesity is also discussed by Rivlin, "The Use of Hormones in the Treatment of Obesity," in Childhood Obesity, ed. Winick (John Wiley & Sons: New York, 1975), pp. 151-162, and Rivlin, Intern. J. Dermatol., 15: 446-449 (1976).
Examples of models showing that administration of GH to obese individuals could stimulate lipolysis include hypophysectomized, ventromedial-hypothalamic-lesionedrats, where GH prevented both hyperphagia and development of obesity (York and Bray, Endocrinology, 90: 885-894 [1972]), and genetically obese Zucker fa/fa rats, which had reduced lipid deposition. Martin and Jeanrenaud, Int. J. Obesity, 9: 99-104 (1985). See also Williams and Frohman, Pharmacotherapy, 6: 311-318 (1986) and Rivlin, New. Engl. J. Med., 292: 26 (1975).
Several studies of GH administration to GH-deficient children, many of whom are obese, demonstrated that one of the earliest and most noticeable changes was loss of adipose tissue. Novak et al., Mayo Clin. Proc., 47: 241-246 (1972); Collipp et al., Metabolism, 22: 589-595 (1973); Parra et al., Metabolism, 28: 851-857 (1979). In addition, obese adults have elevated free fatty acids, indicating increased lipolysis, in response to an injection of GH. Mautalen and Smith, J. Clin. Endocrinol., 25: 495-498 (1965); Blasse, Diabetologia, 4: 20-25 (1968); Bray, Metab., 29: 119-122 (1969).
Further, GH injection to obese patients on a high carbohydrate diet produced more body fat loss than injection of vehicle. Snyder et al., J. Clin. Endocrin. Metab., 69: 745 (1989). It had also been found that exogenous GH reduced body fat and increased fat-free mass in older women that have an impairment in endogenous GH release (Crist et al., Metabolism, 36: 1115-1117 [1987]), and in normosecretory physically fit adults. Crist et al., J. Appl. Physiol., 65: 579-584 (1988). These changes occurred without dietary modification or alterations in physical activity patterns. GH was reported by at least one group to increase the oxidation of fat during caloric restriction. Bray, J. Clin. Endocrinol. Metab., 29: 119 (1969). However, others (Clemmons et al., J. Clin. Endocrinol. Metab., 64: 878-883 [1987]; Snyder et al., J. Clin. Endocrinol. Metab., 67: 54-61 [1988]; Snyder et al., Am. J. Clin. Nutr., 52: 431-437 [1990]) have not found a GH-induced enhancement of body fat loss when the hormone was administered to obese adults during a program of caloric restriction. It was found that exogenous GH reduces body fat in obese women in the apparent absence of significant kilocaloric restriction, which effect is unrelated to endogenous GH secretion or body composition. Skaggs and Crist, Horm. Res., 35: 19-24 (1991).
Some of the manifestations of aging, including expansion of adipose-tissue mass, have been shown to be reduced by GH treatment three times a week. Rudman et al., N. Eng. J. Med., 323: 1-6 (1990); Crist et al., Metabolism, 36: 1115-1117 (1987).
IGF-I is reported to lower blood glucose levels in rats and humans for use in treating diabetes and the secondary effects of hyperinsulinemia, including obese subjects. Froesch et al., TEM, May/June 1990, p. 254-260; Guler et al., N. Engl. J. Med., 317: 137-140 (1987); U.S. Pat. No. 4,988,675 issued Jan. 29, 1991; Carisson et al., J. Endocrin., 122: 661-670 (1989); Zenobi et al., J. Clin. Invest., 89: 1908-1913 (1992). In contrast to GH, IGF-I and insulin have a known anti-lipolytic effect. Zapf et al., J. Clin. Invest., 77: 1768-1755 (1986); Guler et al., N. Engl. J. Med., 317: 137-140 (1987); Zapf et al, Eur. J. Biochem., 87: 285-296 (1978); Bolinder et al., Clin. Endocrinol. Metab., 65: 732-737 (1987); Giacca et al., Diabetes, 39: 340-347 (1990). Further, it has been observed that obese Zucker rats are resistant to the effects of IGF-I and insulin on glucose and amine acid metabolism. Jacob et al., Diabetes, 41: 691-697 (1992).
The most recent study of the effect of IGF-I on body composition was by Certain et al. (Endocrinology, 130: 2924-2930 [1992]), who injected recombinant human IGF-I (three times a day at 150 .mu.g/kg/day for 8 weeks) in castrate male sheep fed a pelleted and lucerne chaff diet. Treatment caused plasma IGF-I levels to rise, plasma insulin to fall, and tibia, spleen, and kidney weights to increase. However, despite IGF-I having obvious efficacy, it had no detectable effect on body fat. These authors state that their results are consistent with their earlier studies (Siddiqui et al., J. Endocrinol., 124: 151-158 [19901]) showing similar body composition at equal body weights in mice selected for high and low plasma IGF-I concentrations. They conclude that the effects of GH on reducing body fat are not mediated solely through circulating IGF-I.
In another study, a catabolic state was induced in young rats by diabetes, dexamethasone, or intestinal resection, and then the catabolic animals were treated with IGF-I or IGF-I analogues. Ballard et al., in Modern Concepts of Insulin-Like Growth Factors, ed. Spencer, p. 617-627 (1991). The authors reported that the IGFs caused a trend toward a lower percentage of body fat.
In a long-term study (Guler et al., Acta Endo., 121: 456-464 [1990]), mini-poodles were treated for 130 days with 6 mg/day of recombinant human IGF-I. There was no change in overall body growth but there was a reduced body mass index, which the authors suggest might have been caused by IGF-I. However, they state that this suggestion is to be interpreted with great caution, and that recombinant human IGF-I may well alter carbohydrate and lipid metabolism in the opposite direction of GH.
In the hypophysectomized rat, IGF-I treatment, at doses that caused a large increase in body and organ weights, had no effect on the chemical composition of the skin or carcass. In particular, the percentage of fat was not changed by IGF-I treatment. Clark and Cronin, Abstract D8, 2nd International IGF Symposium, San Francisco, Calif., 1991.
In a recent review summarizing the accumulated knowledge at that time of insulin and IGF-I activity on different tissues (Froesch et al., TEM, 254-260 [May/June 1990]), it is stated on page 256 that small doses of IGF-I may be expected not to affect adipose tissues and this was observed in the rat. They also state that IGF-I administration to the rat in vivo had much more marked effects on muscle than on adipose tissue, citing Zapf et al., J. Clin. Invest., 77: 1768 [1986]. In humans, they state that, compared to insulin, the hypoglycemic potential of IGF-I is relatively greater than its anti-lipolytic potential, citing Guler et al., N. Engl. J. Med., 317: 137 [1987].
It was also found that while insulin-treated hypophysectomized rats increased their food consumption more than untreated hypophysectomized rats (Salter et al., Can. J. Biochem. Physiol., 35: 913 [1957]), food intake in young non-obese dwarf rats was unaffected by either GH or IGF-I infusions. Skottner et al., Endocrinology, 124: 2519-2526 (1989).
Data have demonstrated that many of the effects of GH in rodents are dependent on the pattern in which GH is administered. Robinson and Clark, in Growth Hormone--Basic and Clinical Aspects, eds. Isaksson et al., p, 109-127 (1987). Animals have been treated with GH in many different dose regimes. Continuous infusion of GH has been shown to reduce body fat in the genetically obese Zucker rat. Martin et al., April 1992, FASEB Meeting, Anaheim, Calif. In man, GH regimes of twice daily and daily, and once, twice, and three times a week, and "intermittent" regimes have been tested for their effects on body growth in GH-deficient children. The data demonstrate that frequent injections of GH (daily) are the regime of choice (this is now the accepted regime used in the clinic). The data in the rat also show that frequent injections of GH produce greater bone growth and weight gain than infrequent injections of GH, and that continuous exposure to GH by infusion is not as effective as frequent intermittent injections of GH. However, it has been disclosed that infusions of GH, alone or in combination with IGF-I, in amounts that maintain a continuous effective plasma GH concentration, are necessary to stimulate the immune system (GH-responsive lymphoid tissues) of a host mammal or avian. WO 93/00109 published 7 Jan. 1993.
Considering the high prevalence of obesity in our society and the serious consequences associated therewith as discussed above, any therapeutic drug potentially useful in reducing weight of obese persons could have a profound beneficial effect on their health. There is a need in the art for a drug that will reduce total body weight of obese subjects toward their ideal body weight without significant adverse side effects and that will help the obese subject maintain the reduced weight level.
It is therefore an object of the present invention to provide a treatment regimen that is useful in returning the body weight of obese subjects toward a normal, ideal body weight.
It is another object to provide a therapy for obesity that results in maintenance of the lowered body weight for an extended period of time.
It is yet another object to prevent obesity and, once treatment has begun, to arrest progression or prevent the onset of diseases that are the consequence of, or secondary to, the obesity, such as arteriosclerosis and polycystic ovarian disease.
These and other objects will be apparent to those of ordinary skill in the art.